Low-Dose Metronomic Chemotherapy and Cancer Modalities

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It is interesting how things and topics have a way of coming full circle. I recently had two such instances related to low-dose metronomic chemotherapy.

The first full circle was a recent conversation with a patient who was trying to communicate with her oncologist that she wanted a lower dose of chemotherapy. Why? Well, this patient was dealing with massive bone marrow suppression from the full-dose chemotherapy she was receiving. And, after two doses and poor tolerability, the oncologist told her there was nothing else that could be done as the chemotherapy did not appear to be working. Moreover, the patient had required two hospitalizations secondary to chemotherapy adverse effects. The patient enquired about reducing the chemotherapy dose to improve tolerability, in the hopes of building some momentum in treatment. Sadly, the oncologist gave no approval.

In a second full circle, I interviewed Dr. Jeffrey Jones and Dr. Nasha Winters on my podcast, and we discussed innovation in medicine and how integrative oncology has the capacity to problem-solve and move between lanes, whereas natural, holistic, and conventional oncology are stuck in their own lanes. It was on this podcast, which you can find here on Pre-Scribed, that Dr. Jeffrey Jones highlighted the value of low-dose metronomic chemotherapy for bridging the gap between targeting cancer while preserving the immune system. Imagine such a concept: a therapy that targets the tumor without destroying the immune system.

Integrative Oncology Analogy low-dose metronomic chemotherapy

It reminded me of some work I had done back in 2021 and 2022. So, in this blog post, I decided to bring a blast from the recent past on low-dose metronomic chemotherapy.

Fractionated, metronomic dosing, low-dose metronomic dosing, insulin-potentiated low-dose chemotherapy, and multiple low-dose chemotherapy are recognized as effective, low-dose chemotherapy dosing modification options for the treatment of cancer.

“The term ‘metronomic chemotherapy’ (MTC) is currently used for frequent and regular administration of lower doses of chemotherapeutic drugs with minimal drug-free time intervals, or simply ‘lower doses, longer times,’ in order to establish a prolonged and lower, albeit an active, range of plasma concentration enabling a favorable side-effect profile.”

There is now even a recognized “ultra” low-dose chemotherapy dosing that functions in chemoimmunomodulation.

Immunogenic chemotherapy is a new term in the published literature due to fractionated, metronomic dosing, low-dose metronomic dosing, insulin-potentiated low-dose chemotherapy, and multiple low-dose chemotherapy’s anti-cancer immunomodulatory effects.

The purpose of fractionated, metronomic dosing, low-dose metronomic dosing, Insulin Potentiated low-dose chemotherapy, and multiple low-dose chemotherapy is to administer low-dose, non-toxic chemotherapy at close, regular intervals without significant interruptions. This unique dosing strategy is evidence-based and delicately balances anti-cancer cytotoxicity therapy and tolerability. In some patients, their body and immune system are in no position to handle the massive collateral damage of the nuclear strike of full-dose chemotherapy. Instead, they need a more precise strike, like that found in fractionated, metronomic dosing, low-dose metronomic dosing, Insulin Potentiated low-dose chemotherapy, to limit collateral damage and preserve the ability to continue treatment.

Fractionated, metronomic dosing, low-dose metronomic dosing, Insulin Potentiated low-dose chemotherapy, and multiple low-dose chemotherapy have been shown to:

  1. Reduces chemoresistance
  2. Reduce cytokine storm-associated metastasis through effects in the tumor microenvironment
  3. Stimulates chemoimmunomodulatory anti-cancer effects
  4. Suppresses MDSC and T reg cell-stimulated immunosuppressive activity, which allows an increase in NK and T cell anti-tumor cytotoxicity
  5. Stimulates dendritic cell maturation and anti-tumorigenic activity
  6. Augments dendritic cell therapy
  7. Generates immunogenic cell death
  8. Remodels tumor immune microenvironment
  9. Stimulates immunogenicity
  10. Vascular preservation to improve immune access
  11. Triggers tumor senescence
  12. Cytotoxic to malignant cells
  13. Suppression of tumor angiogenesis
  14. Reduces Vascular Epithelial Growth Factor (VEGF) signaling
  15. Inhibits Hypoxia Inducible Factor-1 alpha (HIF-1alpha) VEGF signaling
  16. Anti-angiogenic
  17. Stimulates anti-tumor immune effects in the Tumor Microenvironment (TME)
  18. Suppresses Myeloid Derived Suppressor Cells (MDSC) immunosuppression
  19. Triggers angiogenic dormancy
  20. Reduces Cancer Stem cells (CSC)
  21. Stimulates malignant apoptosis
  22. Restores chemosensitivity in chemoresistance cancers
  23. Reduced toxicity profile
  24. Induced tumor regression
  25. Prolonged patient survival
  26. Similar efficacy compared to conventional chemotherapy
  27. Reduces metastasis

Fractionated, metronomic dosing, low-dose metronomic dosing, insulin-potentiated low-dose chemotherapy, and multiple low-dose chemotherapy include dosing as low as 10-30% of maximum tolerated chemotherapy dosing. “Ultra-low-dose chemotherapy was found to stimulate chemoimmunomodulation of immune effector cells to target cancer cells.”

Fractionated, metronomic dosing, low-dose metronomic dosing, Insulin Potentiated low-dose chemotherapy, and multiple low-dose chemotherapy have shown efficacy in pre-clinical and clinical trials.

Fractionated, metronomic dosing, low-dose metronomic dosing, Insulin Potentiated low-dose chemotherapy, and multiple low-dose chemotherapy have been shown to provide disease control in advanced cancer i.e., metastatic breast cancer, with lower adverse events compared to maximum tolerated chemotherapy.

Reduced dosages or fractionated doses of chemotherapy are given regularly to patients with metastatic disease, with associated co-morbidities, and at the discretion of the prescribing physician based on the published evidence. Nowhere in the published literature is there a standard agreed upon definition of “low-dose”, other than it is less than maximum tolerated—most in the 10-30% range with 25-30% as being the most often utilized dose. Breast cancer is the most evaluated and published cancer type in the use of fractionated, metronomic, low-dose metronomic, or multiple low-dose chemotherapy.

Though the vast majority of available research is preclinical, there is still strong evidence supporting and warranting consideration of low-dose metronomic chemotherapy in certain clinical situations. Simply stating the limitations of published evidence does not negate its positive aspects. All cancer treatments are balanced between benefits and limitations.

I hope this blast from the past will help you better understand low-dose metronomic chemotherapy. Moreover, if this scourge of a disease ever affects you, your family, loved ones, or friends, I hope this evidence-based information empowers you in your conversations about treatment. An empowered patient is a wonderful thing.

References

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